Project Abstract The long-term objective of this proposal is to determine the physiological role of central ?-klotho in metabolic regulation, establish a previously uncovered signaling pathway of ?-klotho-FGFR1-PI3K in AgRP/NPY or POMC neurons that contributes to neuronal activity associated with obesity and its related diseases. Hypothalamic neurons, particularly the arcuate neurons located in the medial basal part of the hypothalamus, are capable of sensing nutrients and hormones such as glucose, leptin, insulin and lipid, to maintain energy homeostasis. We have preliminary evidence that ?-klotho, a known anti-aging protein, is a novel humoral factor that target hypothalamic neurons, POMC and AgRP/NPY, which regulates energy and glucose metabolism. For example, central administration of ?-klotho decreases food intake, fat mass, body weight, glucose levels and increases energy expenditure in DIO mice. This and other findings lead us to the novel hypothesis that hypothalamic ?-klotho signaling is required for the homeostatic regulation of energy metabolism. The proposed studies will focus on the effects of central ?-klotho on metabolic function in varies mouse models of obesity and diabetes, and the molecular mechanism underlying ?-klotho?s metabolic effects. These include ?-klotho potential targeting POMC and AgRP/NPY neurons and signaling pathways that involve fibroblast growth factor receptor 1 (FGFR1) and the Phosphoinositide 3-kinase (P13 kinase).